Further studies on pyrazolo[1′,5′:1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones as potent and selective human A1 adenosine receptor antagonists

• Pyrazolo[1′,5′:1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones nucleus.
• Human A1, A2A and A3 adenosine receptors binding assays.
• Functional cAMP assay.
• Antiamnesic activity.

A new series of pyrazolo[1′,5′:1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones was synthesized and tested in radioligand binding assays on human A1, A2A and A3 adenosine receptors. Most of the compounds showed high selectivity of action towards A1 receptor and high affinity with Ki values in the low nanomolar range. The pharmacological profile of the most active molecules towards A1 adenosine receptors was evaluated in cAMP functional assay. Compounds demonstrated their ability to completely counteract the effect of the agonist NECA, thus demonstrating their antagonist profile. Moreover, the most interesting compound, tested in the mouse passive avoidance, exhibited an antiamnesic effect at the doses of 10 and 30 mg/kg.

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